Orphanet Journal of Rare Diseases

BioMed Central

Review Open Access

McCune-Albright syndrome
Claudia E Dumitrescu and Michael T Collins*

Address: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National
Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
Email: Claudia E Dumitrescu - mosteanuc@nidcr.nih.gov; Michael T Collins* - mc247k@nih.gov
* Corresponding author

Published: 19 May 2008 Received: 29 November 2007

Accepted: 19 May 2008
Orphanet Journal of Rare Diseases 2008, 3:12 doi:10.1186/1750-1172-3-12
This article is available from: http://www.ojrd.com/content/3/1/12
© 2008 Dumitrescu and Collins; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
McCune-Albright syndrome (MAS) is classically defined by the clinical triad of fibrous dysplasia of
bone (FD), café-au-lait skin spots, and precocious puberty (PP). It is a rare disease with estimated
prevalence between 1/100,000 and 1/1,000,000. FD can involve a single or multiple skeletal sites
and presents with a limp and/or pain, and, occasionally, a pathologic fracture. Scoliosis is common
and may be progressive. In addition to PP (vaginal bleeding or spotting and development of breast
tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other
hyperfunctioning endocrinopathies may be involved including hyperthyroidism, growth hormone
excess, Cushing syndrome, and renal phosphate wasting. Café-au-lait spots usually appear in the
neonatal period, but it is most often PP or FD that brings the child to medical attention. Renal
involvement is seen in approximately 50% of the patients with MAS. The disease results from
somatic mutations of the GNAS gene, specifically mutations in the cAMP regulating protein, Gs alpha.
The extent of the disease is determined by the proliferation, migration and survival of the cell in
which the mutation spontaneously occurs during embryonic development. Diagnosis of MAS is
usually established on clinical grounds. Plain radiographs are often sufficient to make the diagnosis
of FD and biopsy of FD lesions can confirm the diagnosis. The evaluation of patients with MAS
should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing
for each. Genetic testing is possible, but is not routinely available. Genetic counseling, however,
should be offered. Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-
ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm. Treatment is
dictated by the tissues affected, and the extent to which they are affected. Generally, some form
of surgical intervention is recommended. Bisphosphonates are frequently used in the treatment of
FD. Strengthening exercises are recommended to help maintaining the musculature around the FD
bone and minimize the risk for fracture. Treatment of all endocrinopathies is required. Malignancies
associated with MAS are distinctly rare occurrences. Malignant transformation of FD lesions occurs
in probably less than 1% of the cases of MAS.

Definition puberty (PP) [1,2]. It was later recognized that other endo-
Originally, the McCune-Albright syndrome (MAS) was crinopathies, including hyperthyroidism (reviewed in
defined by the triad of polyostotic fibrous dysplasia of [3]), growth hormone (GH) excess [4,5], renal phosphate
bone (FD), café-au-lait skin pigmentation, and precocious wasting with or without rickets/osteomalacia [6] and

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Cushing syndrome could be found in association with the
original triad [7-9]. Rarely, other organ systems may be
involved (liver, cardiac, parathyroid, pancreas) [10].
While MAS is rare, FD is not. FD can involve a single skel-
etal site (monostotic FD, MFD), or multiple sites (polyos-
totic FD, PFD) [11-14]. Very rarely PP can be found in
association with café-au-lait skin pigmentation in the
absence of FD (about 1% of the cases), but in general, FD
seems to be the most common component of MAS. There-
fore, a more clinically relevant definition of MAS, broader
than the original triad of FD + PP + café-au-lait is: MAS =
FD + at least one of the typical hyperfunctioning endo-
crinopathies and/or café-au-lait spots, with almost any
combination possible [13,15].
Epidemiology
MAS is a rare disease and reliable data of prevalence are
not available (the estimated prevalence ranges between 1/
100,000 and 1/1,000,000). In contrast, the skeletal aspect
of the disease, FD, especially monostotic disease, is not
rare [16]. FD has been reported to account for up to 7% of
all benign bone tumors.
Clinical description
Typically, the signs and symptoms of either PP or FD usu-
ally account for the initial presentation. In girls with PP, it
is usually vaginal bleeding or spotting, accompanied by
development of breast tissue, usually without the devel-
opment of pubic hair. In boys, it can be bilateral (or uni-
lateral) testicular enlargement with penile enlargement,
scrotal rugae, body odor, pubic and axillary hair, and pre-
cocious sexual behavior. In retrospect, café-au-lait spots
(Fig. 1), which are usually present at birth or shortly there-
after, are the most common but unappreciated "present-
ing" sign.
Fibrous dysplasia in the appendicular skeleton usually
presents with a limp and/or pain (sometimes reported by
children as being "tired"), but occasionally a pathologic
fracture may be the presenting sign. Radiographs will
demonstrate typical expansile lesions with endosteal scal-
loping and thinning of the cortex with the matrix of the
intramedullary tissue demonstrating a "ground glass"
appearance (Fig. 2A &2B). FD in the craniofacial bones
usually presents as a painless "lump" or facial asymmetry.
Representative radiographic findings and the histological
appearance of FD are shown in Figures 2 and 3. The areas
most commonly involved are the proximal femora and
skull base. The sites of FD involvement are established
early; 90% of the total body skeletal disease burden is usu-
ally established by age 15 [17]. Hart et al. found that
lesions in the craniofacial region were established earliest,
with 90% of the lesions present by 3.4 years of age. In the
extremities, 90% were present by 13.7 yr, and in the axial
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Figure 1 skin pigmentation
Café-au-lait
Café-au-lait skin pigmentation. A) A typical lesion on the
face, chest, and arm of a 5-year-old girl with McCune-
Albright syndrome which demonstrates jagged "coast of
Maine" borders, and the tendency for the lesions to both
respect the midline and follow the developmental lines of
Blashko. B) Typical lesions that are often found on the nape
of the neck and crease of the buttocks are shown (arrows).
skeleton, 90% were present by 15.5 yr. The appearance of
new lesions later in life is a very uncommon occurrence in
FD. The incidence of fractures is greatest in childhood,
between the age of 6 and 10 yr, but due to the intrinsic
abnormalities in FD bone, some fractures continue to
occur into adulthood (Fig. 4)[18].
Other features of the presentation related to the specific
aspect of the disease are outlined in Table 1.
Malignancies in MAS
While malignancies associated with MAS are distinctly
rare occurrences, they warrant mentioning due to their
importance. Malignant transformation of FD lesions is
probably the most common and best described malig-
nancy that occurs in association with MAS [12,16,19].
This occurs in probably less than 1% of the cases of FD/
MAS. High dose external beam radiation is a risk factor for
sarcomatous transformation [19]. There may be a greater
tendency for malignant transformation to occur in
patients who have concomitant GH excess [20]. While
some have suggested that sarcomatous transformation of
skeletal lesions may occur more commonly in patients
with Mazabraud's syndrome (benign intramuscular
myxomas in association with long standing FD) [21], this
may represent selection bias.
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Figure 2
Radiographic appearance of fibrous dysplasia (FD)
Radiographic appearance of fibrous dysplasia (FD). A)
A proximal femur with typical ground glass appearance and
shepherd's crook deformity in a 10-year-old child is shown.
B) The appearance of FD in the femur of an untreated 40-
year-old man demonstrates the tendency for FD to appear
more sclerotic with time C) The typical ground glass appear-
ance of FD in the craniofacial region on a CT image of a 10-
year-old child is shown. The white arrows indicate the optic
nerves, which are typically encased with FD. D) A CT image
in a 40-year-old woman demonstrates the typical appearance
of craniofacial FD in an older person, with mixed solid and
"cystic" lesions. The Hounsfield Unit measurements of
"cystic" lesions are quite useful in distinguishing soft tissue
"cystic" lesions from true fluid-filled cysts, which are much
more uncommon and tend to behave aggressively with rapid
expansion and compression of vital structures. E-G) Bone
Scintigraphy in FD. Representative 99Tc-MDP bone scans
which show tracer uptake at affected skeletal sites, and the
associated skeletal disease burden score (see ref. Collins,
2005) are shown. E) A 50-year-old woman with monostotic
FD confined to a single focus involving contiguous bones in
the craniofacial region. F) A 42-year-old man with polyostotic
FD shows the tendency for FD to be predominantly (but not
exclusively) unilateral, and to involve the skull base and prox-
imal femur. G) A 16-year-old boy with McCune-Albright syn-
drome and involvement of virtually all skeletal sites
(panostotic) is shown [65].
In addition, the risk of breast cancer may be elevated in
patients with MAS [22,23]. Besides the published reports,
in the series of approximately 120 patients seen at the
National Institutes of Health (NIH), the prevalence of
breast cancer was approximately 2.5% (n = 3). In this
group of three patients, there also seems to be an effect of
GH excess, in that all patients who had breast cancer also
had GH excess (unpublished data).
Thyroid cancer [24] and testicular cancer (unpublished
data) are also rare occurrences.
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Etiology
The observation that the G protein/cAMP/adenylate
cyclase signaling pathway was central to all of the tissues
involved in MAS eventually led to the discovery that
mutations in the regulatory Gsα protein (encoded by the
GNAS gene) were the underlying molecular etiology of
MAS [25,26] (Fig. 5). In all published cases of MAS, PFD,
and even MFD, activating mutations of Gsα at the R201
position have been identified [27]. More recently, muta-
tions at the Q227 position have been found in association
with FD [28].
The lack of vertical transmission of the disease, along with
the observation that skin and bone lesions tend to respect
the midline and be on one or the other side of the body,
has led to the unproven, but accepted, concept that the
disease is the result of postzygotic mutations, and that
patients are therefore somatic mosaics. The point in time
in development at which the mutation occurs, the specific
cell in which it occurs, and to where its progeny migrate,
determines what tissues will be affected, and thus the phe-
notype. Therefore, in cases in which tissues of endoder-
mal, mesodermal, and ectodermal origin are involved, it
would appear that the mutation occurred at the inner cell
mass stage (Fig. 6) [29].
Diagnosis, diagnostic criteria, diagnostic
methods, differential diagnosis
Diagnosis of MAS is usually established on clinical
grounds. Plain radiographs are often sufficient to make
the diagnosis of FD (Fig. 2). Isotopic bone scans are the
most sensitive tool for detecting the presence of FD
lesions, and are often useful, especially at the initial eval-
uation, for determining the extent of the disease and pre-
dicting functional outcome (Fig. 4E,F, &4G) [17,30]. FD
has a typical appearance on radiographs described as
"ground glass." In general, lesions in the long bones have
a "lytic" appearance. The lesions usually arise in the med-
ullary cavity and expand outward replacing normal bone,
which results in thinning of the cortex (Fig. 2A &2B). It is
usually the metaphysis and/or the diaphysis that are
involved, with sparing of the epiphysis. It is possible for
any bone to be involved, but the skull base and the prox-
imal femur are the sites most commonly involved
[16,31,32]. Due to the fact that these lesions are under-
mineralized [27], the bones are "soft" and prone to defor-
mation, as exemplified by the classic "shepherd's crook"
deformity of the proximal femur (Fig. 2A).
FD in the craniofacial bones tends to have a "sclerotic"
appearance on plain radiographs. This is due to the rela-
tively greater degree of mineralization of FD tissue in the
craniofacial bones (Fig. 3) [33]. Computed tomography
(CT) scanning is the best technique for imaging FD
lesions in the skull, revealing a "ground glass" appear-
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Figure 3
Representative histological images of FD
Representative histological images of FD. A) Calvarial FD lesions are characterized by uninterrupted networks of bone
trabeculae (b) embedded in the fibrous tissue (ft). B) In FD lesions from gnathic bones, newly formed bone trabeculae (b) are
deposited within the fibrous tissue (ft) in a typical discontinuous and parallel pattern. C) Collagen fibers perpendicularly ori-
ented to forming bone surfaces (Sharpey fibers, arrows) represent a recurrent histological feature of FD at all skeletal sites. D-
E) Osteomalacic changes and FGF23 production in FD. D) In many cases of FD, processing for undecalcified embedding reveals
excess osteoid (asterisks) and severe undermineralization of the fibrous dysplastic bone. E) The mineralization defect of the FD
tissue is related to elevated levels of FGF23 produced by activated FD osteogenic cells (arrows), as shown by in situ hybridiza-
tion.

ance. In children and young adults, the lesions appear

homogeneous on CT, but in older patients the appearance
is mixed, with the development of "cystic" lesions in some
areas. The density of these areas is that of soft tissue, so
while they may have a cystic appearance they are not true
cysts. That said, it is possible for true cysts to develop in
FD, both in the long bones, but more often in the cranio-
facial bones (Fig. 7). This has occurred in about 5% of the
patients with FD in the NIH cohort (unpublished data). If
needed, bone cysts may be diagnosed using magnetic res-
onance imaging (MRI). The cysts tend to have a more
aggressive course. They can expand rapidly and produce
symptoms which vary, depending on the location. One of
the complications can be the fracture through a cyst. This
Figure 4rates in FD
Fracture
usually requires surgical intervention. Fracture rates in FD. Fractures rates (reported as mean
number of fractures per patient per year) are shown. Frac-
Biopsy of FD lesions can confirm the diagnosis if doubt tures are more frequent in childhood, with the highest rate
remains after review of the radiographs. One characteristic occurring between 6–10 years of age. While fractures do
of FD bone is the absence of the lamellation pattern seen lessen after childhood, there is a persistent rate into adult-
in normal bone under polarized light. This indicates that hood [18].

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Table 1: Clinical presentation

Clinical feature Presentation/Feature

Café-au-lait spots appearance: "coast-of-Maine", location: nape of neck, base of spine; usually respect midline; trunk & face more
commonly involved than limbs (Figure 1)
Fibrous dysplasia (FD) phosphatase, medullary cavity of the bone. [16, 18]
Craniofacial FD nerve decompression is contraindicated [40, 41]
Axial FD usually asymptomatic, scoliosis common and possibly progressive [56] rib pain develops late
Appendicular FD often painful in adults, but pain is quite variable [17, 18]
Gonadal – Female Vaginal bleeding, breast development with little or no pubic hair, secondary central PP often develops, GnRH
test [66]
Gonadal – Male common, detectable by ultrasound only, cancer rare, but possible [67]
Thyroid abnormalities ultrasound and biopsy large solid or changing lesions [3], cancer can occur [24]
Phosphaturia worsens pain [6]; etiology is FGF23 of FD bone origin [43]
Growth hormone (GH) excess suggests GH excess, worsens craniofacial FD [5, 41]
Cushing syndrome quite ill, spontaneous resolution possible [9]
Additional clinical features alopecia [70], myxomas and others cutaneous abnormalities [71]

the matrix produced in the lesions is of the woven type.
The histopathological description of FD is often described
as a "Chinese writing" pattern, and with special prepara-
tion and stains used to detect mineralized and unmineral-
ized tissue, extensive areas of unmineralized osteoid are
evident (Fig. 3) [27]. For an extensive description of the
histopathological changes that can be observed in FD, the
reader is referred to Riminucci et al. and Corsi et al.
[33,34].
Genetic testing
Genetic testing is possible, but is not routinely available
(see below). Because of the somatic mosaic nature of the
disease, a negative result from readily available (but unaf-
fected) tissue does not exclude the presence of the muta-
tion. Testing on leukocyte DNA is possible [35], but it is
unreliable. In most cases, genetic testing contributes little

Figure(MAS)
Molecular
drome 5 defect and phenotype in McCune-Albright syn-
Molecular defect and phenotype in McCune-Albright
syndrome (MAS). The hormones MSH (melanocyte stimu-
lating hormone), LH (luteinizing hormone), TSH (thyroid
stimulating hormone), GHRH (growth hormone stimulating
hormone), and ACTH (adrenocrotical stimulating hormone)
all signal through the G protein (alpha, beta, gamma subunits)
pathway. In MAS, the alpha subunit is mutated in such a way
as to induce constitutive activation of adenylate cyclase, and Figure(MAS)
Molecular
drome 6 and developmental defect in McCune-Albright syn-
thus produce high levels of intracellular cAMP. This results in Molecular and developmental defect in McCune-
increased production of melanin, estradiol (E2), testosterone Albright syndrome (MAS). A sporadic mutation occurs in
(T), thyroxine (T4), growth hormone (GH), and cortisol. a single cell (bright spot) at some point early in development.
Dysregulated production of these hormones results in café- If this occurs at the inner call mass stage (embryonic stem
au-lait spots, precocious puberty, fibrous dysplasia, acromeg- cell stage), tissues from all 3 germ layers will be affected. As
aly, hyperthyroidism, and Cushing's disease, depending on the the cells derived from this mutated clone are dispersed
tissue harboring the somatic mutation. throughout the organism, the final phenotype emerges, MAS.

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Figure 7 cyst in FD
Fluid-filled
Fluid-filled cyst in FD. True fluid-filled cysts can occur in
FD lesions. Shown is the CT scan of fluid-filled cyst that
arose in a 12 year old boy with MAS who presented with
facial nerve parasthesias and displacement of the orbit that
occurred over approximately one week. The fluid-filled
nature of the lesion is demonstrated by the fluid-fluid level
(arrow). These lesions are more frequent in the craniofacial
bones and can be aggressive. They usually require prompt
surgical intervention.
to the diagnosis and not at all to management. There is no
known genotype/phenotype correlation, so knowledge of
the specific mutation does not affect management. For
this reason, when the diagnosis of MAS is suspected or
established, it is important to be cognizant of the spec-
trum of tissues that possibly can be involved, and to
screen for involvement. Screening, at a minimum,
requires a medical history and physical examination, and
usually involves specific imaging and biochemical testing.
The following are listed as potential sources for genetic
testing: Center for Genetic Testing at Saint Francis [36],
Genome Diagnostics [37]. In addition, the research labo-
ratories of Professors Francis Glorieux, Shriners Hospital
for Children (Montreal, Canada), Paolo Bianco (Rome,
Italy) and Charles Sultan (Montpellier, France) can per-
form genetic testing on a research basis.
Differential diagnosis
MAS is most commonly confused with neurofibromatosis
(NF), usually when a child presents with a large café-au-
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lait spot. The location and shape of the spots usually can
help to distinguish between the MAS and NF. The spots in
MAS have jagged borders (coast of Maine), whereas those
in NF are smooth (coast of California). Although the spots
can cross the midline, more often, they demonstrate a
"respect" of the midline. Frequent locations are the nape
of the neck and the crease at the apex of the buttocks (Fig.
1). In MAS, the skeletal disease (PFD) almost always
involves one or both proximal femurs and/or the skull
base, as well as other locations. Skeletal involvement in
NF is uncommon and usually involves the diaphyses of
the long bones, especially the tibiae, often leading to
pseudoarthrosis [38,39].
When precocious puberty is the presenting sign, the differ-
ential diagnosis includes idiopathic central precocious
puberty, and an ovarian neoplasm. Suppressed gonado-
tropins exclude central PP. Other components of the MAS
(skin pigmentation, skeletal changes on x-ray or bone
scan, etc.) can help to assure the clinician that the ovarian
cyst is not neoplastic.
Isolated skeletal lesions in the absence of skin or endo-
crine findings represent FD (MFD or PFD). Osteofibrous
dysplasia (ossifying fibroma of long bones, so-called
Campanacci's lesion) may be confused with FD. These
lesions are almost exclusively found in the tibia and fib-
ula, and are histologically distinct from FD [12]. Non-
ossifying fibromas (NOF) may also share radiological and
histological similarities with FD in the long bones. Lack of
multiple skeletal foci and absence of extraskeletal findings
may help to distinguish FD from NOF. FD in the jaw may
share several histological features with cemento ossifying
fibromas, which can be confused with FD. The cemento
ossifying fibroma lesions tend to behave more aggres-
sively than do FD lesions. Testing for the GNAS mutation,
if tissues and assays are available, may be helpful in distin-
guishing cemento ossifying fibroma lesions from FD.
Specific diagnostic considerations and follow-up
A. Skeletal
Skeletal disease, especially involving the skull base, is very
common. Vision and/or hearing loss are uncommon, and
sarcomatous transformation is rare (<1%). FD in the
appendicular skeleton tends to quiet with age, but the
course of craniofacial disease is less clear [18,40]. Nuclear
medicine bone scans are useful for not only detecting the
extent of the disease, but quantifying the skeletal disease
burden of FD and predicting functional outcome [30].
1. Craniofacial FD
CT scan of the skull is the most useful test for diagnosis of
craniofacial FD (Fig. 4). CT should be repeated periodi-
cally, annually then less frequently once stability has been
demonstrated. Vision should be evaluated, ideally by a
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neuro-ophthalmologist initially, then periodically; annu-
ally or less frequently once stability has been demon-
strated. Hearing evaluation is recommended at baseline to
assess involvement and should also be repeated periodi-
cally. All endocrinopathies which adversely affect bone
should be screened for and treated. GH excess in particu-
lar may adversely affect craniofacial FD [5,40,41]. 99Tc-
methyl diphosphonate (99Tc-MDP) bone scan at baseline
and periodically is recommended.
2. Axial and appendicular skeleton
Plain radiographs, demonstrating the classic ground glass
appearance, are usually sufficient for the diagnosis of FD
in the axial and appendicular skeleton (the axial skeleton
is comprised of bones of the skull, hyoid bone, vertebra,
sternum and ribs; the appendicular skeleton includes the
hip, pelvic bone and the shoulder girdle (clavicle and
scapula) (Fig. 2). However, x-rays are often unable to
detect new, small microfractures. When new focal pain
develops in an FD lesion and no fracture is evident on
plain radiograph, CT and or MRI can be useful for detect-
ing subtle fractures (Fig. 8). The classic lesion of the prox-
imal femur in FD, the shepherd's crook deformity is
common (Fig. 2).
Figure
CT for detecting
8 subtle fractures
CT for detecting subtle fractures. A) This radiograph
was from a 9-year-old boy who complained of new-onset,
focal pain in the groin. No discernable fracture is apparent.
B) Reformatted CT images of the lesion revealed a fracture
in the medial proximal femur (arrows).
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B. Endocrine
1. Gonads
PP is more common in girls then boys. However, small
testicular masses of Leydig and/or Sertoli cell hyperplasia
are common in boys. These are usually never detected on
physically examination. Therefore, ultrasound of the tes-
tes is recommended in all males with FD and MAS. It is
probably safe to monitor testicular masses without surgi-
cal intervention as cancer is probably quite rare. The PP of
MAS in girls is due to high levels of serum estradiol due to
intermittent autonomous activation of ovarian tissue.
Some of them will progress to central PP, secondary to
activation of the hypothalamic-pituitary-gonadal (HPG)
axis. Since central PP usually develops in children who
have had PP for some years, children with PP should be
evaluated for secondary central PP.
2. Thyroid
Hyperthyroidism is common (38%) [3]. Evidence of thy-
roid involvement without frank hyperthyroidism is even
more common (63% in the NIH series, unpublished
data). This is manifested as a relatively suppressed thyroid
stimulating hormone (TSH) with elevated Triiodothyro-
nine (T3+) and an abnormal thyroid gland on ultrasound.
Some of these patients may go on to develop frank hyper-
thyroidism, therefore, follow-up with measurement of
TSH, free thyroxine (FT4), T3, and thyroxine (T4), and
periodic ultrasound is recommended to detect those
patients that progress to frank hyperthyroidism. While the
development of thyroid cancer in patients with MAS is
rare [24], patients should be monitored for this possibil-
ity. This is accomplished by annual ultrasound of the thy-
roid. The ultrasonographic appearance of the thyroid in
MAS is complicated [42]. There are usually admixed areas
of relatively normal appearing thyroid with adjacent cystic
areas. Suspicion for cancer should be raised if a large or
expanding solid lesion is noted. This should prompt fine
needle aspiration with cytopathological evaluation.
3. Renal phosphate wasting
Renal phosphate wasting, as part of a proximal tubulopa-
thy, with or without hypophosphatemia, and/or rickets/
osteomalacia is common [6]. The etiology is likely due to
elaboration of the phosphaturic factor, fibroblast growth
factor-23 (FGF23), by FD tissue [43]. Measurement of
serum phosphate and calculation of renal phosphate han-
dling by either the tubular reabsorption of phosphate
(TRP) or maximal tubular reabsorption of phosphate per
glomerular filtration rate (TmP/GFR) are recommended.
While it is debatable whether or not hypophosphatemia,
per se, should be treated, or if treatment should be reserved
for only patients with rickets or biopsy-proven rickets
[44,45], it is our feeling that frank hypophosphatemia
should be treated (see Additional file 1).
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Figure 9 of Cushing in a neonate
Appearance
Appearance of Cushing in a neonate. Rounded (moon)
facies with plethora and facial hirsutism are present. This is
usually accompanied by the presence of typical café-au-lait
spots elsewhere on the examination.
4. Pituitary
GH and prolactin excess are common (21%), and the
signs and symptoms can be very subtle. Since GH excess
can worsen craniofacial bone disease [5,40,41], it is
important to make the diagnosis and treat. All patients
should have an oral glucose tolerance test (OGTT) to look
for non-suppressible GH at least once. Most GH secreting
tumors are co-secretors of GH and prolactin, so prolactin
levels should also be assessed, as hyperprolactinemia can
independently have an adverse affect on gonadal func-
tion.
5. Parathyroid
Primary hyperparathyroidism in MAS is rare and is prob-
ably not a part of the syndrome [46]. Secondary hyperpar-
athyroidism, usually due to vitamin D deficiency is
common in the general population as well as in FD/MAS
[47-50]. Hyperparathyroidism can worsen FD and should
be treated [34]. Total or ionized serum calcium and par-
athyroid hormone (PTH) need to be assessed periodically.
6. Adrenal
Cushing syndrome can occur in the neonatal period, but
has not been reported past the first year. Some cases of
neonatal Cushing resolve spontaneously [9]. Cushing
syndrome must be considered and screened for in very
young patients. The physical examination is usually sug-
gestive and shows moon facies with plethora, hirsutism,
and lack of linear growth (Fig. 9). If suspected, laboratory
evaluation with some combination of a 24-hour urine for
urinary free cortisol (if possible), midnight, or salivary
cortisol, and/or dexamethasone suppression test are indi-
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cated. Adrenal reserve should be checked in patients in
whom Cushing resolved spontaneously (personal com-
ment, in the NIH series 2 out of 9 patients with Cushing
had spontaneously cure and inadequate adrenal reserve
later in life).
Genetic counseling
The most important aspect of counseling families is to
assure the patients or families that there is no vertical
transmission of the disease, nor are there any known envi-
ronmental associations or predilection for ethnic groups.
Therefore, parents need not feel "responsible," and
patients can be assured they will not transmit the disease
to their offspring.
Antenatal diagnosis
Not relevant.
Management, treatment, and prognosis
A. Skeletal
1. Craniofacial FD
In the vast majority of cases of craniofacial FD, surgery is
not needed, and observation is the correct approach.
Observation involves annual vision and hearing testing,
and imaging. Vision should be checked by a neuro-oph-
thalmologist. CT of skull and/or mandible is the imaging
test of choice for the cranial structures in general, but MRI
will give better resolution of the optic nerves. Cranial
nerves are often surrounded by FD bone, but remain unaf-
fected for years to decades [41]. Indications for surgery
include documented progressive visual disturbance,
severe pain, or severe disfigurement. Surgery should be
avoided in the absence of visual or hearing impairment.
However, when surgery is indicated, it is very important to
find a craniofacial and neurosurgical team experienced in
treating craniofacial FD. It is possible the craniofacial dis-
ease may continue to progress slowly into adulthood, but
this subject has not been well studied in a prospective
manner [40].
There is little evidence that bisphosphonates are effective
in craniofacial FD, even for pain, but in the case of pain
that is difficult to manage, bisphosphonate treatment
should be considered (Additional file 2).
2. Axial and appendicular skeleton
The surgical management of FD has evolved over the
years. While curettage and bone grafting were once con-
sidered the treatment of choice, experts in the care of FD
no longer feel this is effective [31,51]. Intramedullary
devices are preferable, in general [31,51]. Bracing may be
helpful, but has not been well-studied. Shepherd's crook
deformity can develop, sometimes very rapid, and the
management in growing children is very challenging.
Generally, some form of surgical intervention is recom-
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Orphanet Journal of Rare Diseases 2008, 3:12
mended. Screening for and treatment of all endocrinopa-
thies which adversely affect the skeleton should be
performed [34]. This includes PP, hyperthyroidism, Cush-
ing's syndrome, GH excess, and secondary hyperparathy-
roidism.
Bisphosphonates are frequently used in the treatment of
FD (reviewed in [45,52]. The original thinking in the use
of bisphosphonates in FD was that they would prevent the
progression of disease [53]. However, more recent work
concludes that bisphosphonates have no effect on the nat-
ural history of the disease [54,55]. It is clear, however, that
bisphosphonates are effective in relieving bone pain asso-
ciated with FD [32,45,52]. Many regimens have been sug-
gested. The long term safety of bisphosphonates,
especially in children, and the effects of relatively high
doses of bisphosphonates on normal bone not affected by
FD, are unknown. Therefore, to minimize exposure, our
approach has been to use the minimum dose with the
longest interval between doses possible needed to achieve
and maintain pain relief (Additional file 2).
Maintaining the musculature around the FD bone is
important for protecting the bone. Therefore, strengthen-
ing exercises and strength maintenance is important.
Swimming and cycling are excellent modes of exercise for
patients with FD that will promote strengthening and
minimize the risk for fracture.
Scoliosis is common, and may be progressive [56]. There-
fore, it is important to screen for the presence of scoliosis
and monitor for any progression. Significant progression
can occur within a short period of time.
B. Endocrine
1. Gonads
The management of PP in boys and girls is detailed in
Additional file 3. The class of drugs with the longest his-
tory of safety and efficacy are the aromatase inhibitors
[57,58]. More recently, the estrogen antagonist/agonist,
tamoxifen, has also shown promise [59]. Secondary cen-
tral PP in children with MAS frequently develops after a
period of PP. Its manifestation is often pubertal progres-
sion in a child that had previously been well-controlled
on medical therapy. The treatment of secondary central PP
in children with MAS is the same as in children with idio-
pathic PP, and involves the use of long-acting gonadotro-
pin releasing hormone analogues.
Ultrasound is used to screen and follow boys and men
with testicular masses. These are usually Leydig tumors,
but testes can demonstrate a mixture of Leydig and Sertoli
cell masses. Microlithiasis is also commonly seen. The
development of malignancy in the testes of men with MAS
appears to be very rare. Therefore, prudent management
http://www.ojrd.com/content/3/1/12
may be observation with annual testicular ultrasounds,
and CT of the chest abdomen and pelvis if there is any sus-
picion for malignancy. Lesions should be followed annu-
ally with ultrasound. There are no reported cases of
gynecological malignancy in females with MAS.
2. Thyroid
Antithyroidal medications, such as thionamides, are usu-
ally effective in controlling hyperthyroidism in MAS [60].
Spontaneous resolution of hyperthyroidism in MAS
almost never occurs, so some form of definitive treatment,
either in the form of surgery or radiation, is eventually
indicated. Periodic ultrasounds of the thyroid to follow
lesions should be performed annually. If a dominant or
changing lesion is identified, fine needle aspiration is
indicated to exclude cancer, given that thyroid cancer can
be seen in the setting of MAS [24].
3. Renal
Renal involvement, in the form of renal phosphate wast-
ing, is seen in approximately 50% of the patients with
MAS [6]. However, only some of those patients will have
a degree of phosphate wasting that results in hypophos-
phatemia (18% of the total population seen at NIH). It is
debatable whether the hypophosphatemia warrants treat-
ment with oral phosphorus supplementation if signs of
rickets are absent [44]. However, we recommend that
patients with frankly low serum phosphate should be
treated. Treatment is the same as that for patients with X-
linked hypophosphatemia and tumor induced osteoma-
lacia: high dose of oral phosphate with high dose of calci-
triol (Additional file 1).
4. Pituitary
GH excess is seen in approximately 20% of the patients
with MAS [5]. GH excess has been shown to be associated
with vision and hearing loss, and macrocephaly in
patients with MAS [41]. For that reason, patients with GH
excess and an elevated insulin-like growth factor-1 (IGF-
1) should be treated. Treatment options include medica-
tions, surgery, and radiation. Effective medical treatment
includes long-acting somatostatin analogues [4,5] and the
GH receptor antagonist, pegvisomant [61-63]. There is
greater long-term efficacy and safety with the somatosta-
tin analogues, especially in children. Pegvisomant is sig-
nificantly more expensive than the somatostatin
analogues and may be associated with more side effects
[61]. The goal of treatment in a growing child is to reduce
the calculated serum IGF-1 Z-score to 0.
Surgery is an option, but is sometimes not possible due to
the massive thickening of the skull bones. A trans-sphe-
noidal approach is the preferred method in pituitary sur-
gery, but the skull base is virtually always involved with
FD in patients with MAS and GH excess, so this approach
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Orphanet Journal of Rare Diseases 2008, 3:12
is often impossible, or difficult, at best. A trans-frontal
approach is a less desirable approach to the pituitary, in
general, and in MAS it is also usually complicated by FD.
Furthermore, in patients with MAS and GH excess the
pituitary gland is almost always diffusely involved with
areas of hyperplasia and adenoma (Edward Oldfield, per-
sonal communication). Therefore, the only hope for
"cure" of the GH excess is a total hypophysectomy. This
may be the best treatment in some cases, but physicians,
surgeons, and patients should embark upon this option
knowing that the patient will be rendered panhypopitui-
tary at the end of the operation.
Radiotherapy is an option when surgery is not possible
and medicinal treatment fails. However, there may be a
higher risk of sarcomatous transformation [19,62].
Since most of the GH secreting tumors co-secrete prolac-
tin [5], dopamine agonists (cabergoline, etc.) are usually
necessary, and are effective at normalizing the serum pro-
lactin.
5. Parathyroid
While primary hyperparathyroidism has been reported to
be part of the syndrome in the past [64], this may not be
the case. When the mutations that cause MAS were sought
in parathyroid tissue, they were not present [46]. Addi-
tionally, parathyroid hormone secretion and hyperplasia
is likely not a cAMP, Gsα mediated phenomenon. Second-
ary hyperparathyroidism due to vitamin D deficiency is
common and can worsen FD [34]. Therefore, it should be
screened for and treated.
6. Adrenal
Cushing syndrome is one of the rarest, but most profound
manifestations of MAS. In some cases, it can resolve spon-
taneously [9], but in most cases treatment is required, and
in some cases, in spite of the best of care, it can be fatal.
Adrenalectomy is probably the treatment of choice. If the
child is too ill, adrenal blockade may provide stabilization
of the disease and buy time until a point in time when sur-
gery can be performed. Liver function abnormalities usu-
ally accompany neonatal Cushing syndrome, so
ketoconazole as a medicinal therapy is usually not an
option. Metryrapone at an initial dose of 300 mg/m2/day
is recommended. The dose may be escalated to as high as
1200 mg/m2/day. In patients with a history of neonatal
Cushing, adrenal reserve should be checked. Cushing syn-
drome in MAS is usually accompanied by hyperthy-
roidism, which, if not treated, can complicate and worsen
the clinical course.
Unresolved questions
While bisphosphonates are usually effective in relieving
FD-related pain, whether or not the treatment of FD with
http://www.ojrd.com/content/3/1/12
bisphosphonates changes the natural history of the dis-
ease remains an open question. The most recent, and
strongest data to date, suggests that they do not [54].
Ongoing placebo controlled trials in the US and Europe,
should help to resolve this open question. More effective
treatment for FD is needed. The development of cell based
and/or Gsα directed therapies may hold promise.
The best treatment for PP is also not clear. Letrozole, a
potent third generation aromatase inhibitor, has recently
been shown to be an effective therapy in some girls with
MAS [57]. Studies suggest tamoxifen, the estrogen ago-
nist/antagonist, may also be effective [59]. However, all
trials for the treatment of PP have been uncontrolled, and
this fact, combined with the extreme variability in the
clinical course of the disease, makes conclusions about
relative efficacy very difficult. A trial with the pure anti-
estrogen, fulvestrant, in girls with MAS is underway. Con-
trolled and head-to-head comparison trials are needed to
establish the best treatment for PP in MAS.
Support
A list of groups that support patients, families, and clini-
cians caring for patients with MAS is supplied in Addi-
tional file 4.
Abbreviations
FD: fibrous dysplasia of bone; PP: precocious puberty;
GNAS: G protein binding adenylyl cyclase stimulatory;
cAMP: cyclic adenosine monophosphate; Gs alpha: G pro-
tein α-subunit; MAS: McCune-Albright syndrome; GH:
growth hormone; NF: neurofibromatosis; NOF: Non-ossi-
fying fibromas; CF: craniofacial; TSH: thyroid stimulating
hormone; FT4: free thyroxine; T3: triiodothyronine; T4:
thyroxine; FGF-23: fibroblast growth factor-23; TRP: tubu-
lar reabsorption of phosphate; TmP/GFR: maximal tubu-
lar reabsorption of phosphate per glomerular filtration
rate; OGTT: oral glucose tolerance test; MRI: magnetic res-
onance imaging; CT: computed tomography; IGF-1: insu-
lin-like growth factor-1; PTH: parathyroid hormone;
MSH: melanocyte stimulating hormone; LH: luteinizing
hormone; GHRH: growth hormone stimulating hor-
mone; ACTH: adrenocrotical stimulating hormone; E2:
estradiol; T: testosterone; 99 Tc-MDP: Technetium 99
methylene diphosphonate
Competing interests
The authors declare that they have no competing interests.
Consent
Written informed consent was obtained from the parents
of the patients for publication of this case report and any
accompanying images. A copy of the written consent is
available for review by the Editor-in-Chief of this journal.
Page 10 of 12
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Orphanet Journal of Rare Diseases 2008, 3:12
Additional material
Additional file 1
Recommendations for treatment of hypophosphatemia in MAS. This file
describes the goal, treatment regimen and possible complications.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1750-
1172-3-12-S1.doc]
Additional file 2
Bisphosphonate treatment. This file describes the goal, regimen and possi-
ble complications of bisphosphonate treatment.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1750-
1172-3-12-S2.doc]
Additional file 3
Treatment of precocious puberty. This file describes treatment of preco-
cious puberty in girls and boys.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1750-
1172-3-12-S3.doc]
Additional file 4
Support. This file lists groups that support patients, families, and clini-
cians caring for patients with MAS.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1750-
1172-3-12-S4.doc]
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